1. Field
This disclosure relates generally to monoclonal antibodies and specifically with human antibodies that bind to human tumor necrosis factor (TNF.alpha.).
2. Prior Art
TNF.alpha. is a pluripotent and pleiotropic cytokine. It is produced principally by activated macrophages, however its synthesis and secretion have also been observed using granulocytes, tonsil B cells, B cell lines, natural killer cells, T cell lines, primary chronic malignant B cell isolates, and peripheral blood T cells.
TNF.alpha. can also be expressed on cell surfaces, apparently in two forms. One is a 26 kd molecular weight integral type 2 transmembrane protein on monocytes, T cells and some other cells. The other form is the secreted 17 kd product which is bound to its receptor.
Among the many activities of secreted TNF.alpha. are thymocyte growth factor, B cell growth and maturation factor, production in vivo of hemorrhagic necrosis, weight loss, cardiovascular collapse and multiple organ failure. Naturally, these latter activities are the source of the clinical interest in TNF.alpha..
During septic shock, as well as inflammatory diseases, synthesis and secretion of TNF.alpha., IL-1, IL-6 and IL-8 have been documented. Hence the immune systems of some individuals are exposed chronically to these cytokines. Indeed, low affinity antibodies to TNF.alpha. have been reported (A. Fomsgaard et al "Auto-antibodies to Tumor Necrosis Factor .alpha. in Healthy Humans and Patients with Inflammatory Diseases and Gram-Negative Bacterial Infections." Scand. J. Immunol. 30:219-23, 1989; and, K. Bendtzen et al "Auto-antibodies to IL-1.alpha. and TNF.alpha. in Normal Individuals and Infectious and Immunoinflammatory Disorders." Prog. Leukocyte. Biol. 10B:447-52, 1990). These anti-TNF.alpha. autoantibodies may, however, not be specific (H. -G. Leusch et al "Failure to Demonstrate TNF.alpha. Specific Autoantibodies in Human Sera by ELISA and Western Blot." J. Immunol. Meth. 139:145-147, 1991).
One peculiar feature of human serum, as well as sera from other animals, is its content of natural and so-called polyreactive antibodies. These are usually IgM antibodies which bind to various autoantigens with low affinity (A. B. Hartman et al "Organ Reactive Autoantibodies from Non-Immunized Adult Balb/c Mice are Polyreactive and Express Non-Biased Vh Gene Usage." Molec. Immunol. 26:359-70, 1989; and, P. Casali et al "CD5+ B Lymphocytes, Polyreactive Antibodies and the Human B cell Repertoire." Immunol. Today. 10:364-8, 1989). Hence the autoantibody-like reactivity to human TNF.alpha. might be expected to be low affinity and probably cross-reactive with several other antigens.
Some high affinity neutralizing antibodies to IL-1.alpha. have been reported in normal sera (N. Mae et al "Identification of High-Affinity Anti-IL-1.alpha. Autoantibodies in Normal Human Serum as an Interfering Substance in a Sensitive Enzyme-Linked Immunosorbent Assay for IL-1.alpha.." Lymphokine Cytokine and Research 10:(1) 61-68, 1991) or patient (H. Suzuki et al "Demonstration of Neutralizing Autoantibodies Against IL-1.alpha. in Sera from Patients with Rheumatoid Arthritis." J. Immunol. 145:2140-6, 1990).
Despite these considerations, we are unaware of the disclosure of any monoclonal human antibodies specifically binding to TNF.alpha. even though it is thought such antibodies may have significant clinical value. Thus, there has remained a need for monospecific monoclonal antibodies to TNF.alpha..